ABSTRACT Despite significant advances in survival and the decreased risk of major brain injury in premature infants, the persistent high prevalence of long-term remains a major public health problem, with enormous personal, familial, and societal costs. There is growing evidence that impaired structural brain development is detectable in premature infants before term corrected age, even without overt destructive brain injury. Together these observations suggest that brain dysmaturation in an artificial ex-utero environment disturbs neuropsychological development in prematurity survivors. In turn, this points to ongoing gaps between the effectiveness of current support/protection strategies for ex-utero preterm brain development, and that provided by the normal in-utero environment. Critical to closing this gap is identifying the disruptive interactions between the complex shifting landscape of brain maturation/vulnerability, and preterm ex-utero exposures, among which circulatory and oxygenation (C/O) exposures are considered a leading cause of neuropsychologic impairment. To approach this challenge the necessary steps are: to identify the earliest deviations of ex-utero brain maturation compared to normal in-utero brain maturation; to identify the temporal relationship between the onset of brain dysmaturation and preceding C/O exposures; and, to confirm that the early preterm maturational changes predict structural brain development at term-corrected age, and later functional outcome. To date, progress has been impeded by (i) the lack of reference data for normal in-utero brain development, (ii) the lack of serial measurements of ex-utero preterm brain development, and (iii) the lack concurrent biomarkers that capture continuous C/O exposures. Using our large repository of normal in-utero brain development and multimodal quantitative MRI, our preliminary studies show significant anatomic differences in brain development occurring in utero vs. ex utero, detectable well before term-equivalent age. We have developed systems for measuring and analyzing continuous physiological signals in sick preterm infants. In this proposal we combine serial 4- weekly MRI with concurrent exposure measurements in infants born <36 weeks gestation, to establish the relationship between disturbed early brain maturation, specific preterm C/O exposures, and their association with long-term neuropsychological impairment. These findings may inform future brain-oriented support of premature infants, identify specific targets for neuroprotection, and lead to improved neuropsychological outcomes.